We have continued our efforts to develop in vivo and in vitro models to better understand the mechanistic role of genes highly differentially expressed in lung cancers. We have generated transgenic mice carrying a gene, PGP9.5, which is frequently over expressed in lung cancers. We are collaborating with Dr. Ilona Linnoila's laboratory to examine these transgenic animals for transgene expression as well as potential lung carcinogenesis and interactions with other lung tumor animal models. To date, we have identified a founder animal that carries lung specific expression of the PGP9.5 gene. These animals are now being bred for Dr. Linnoila's laboratory as an collaboration to address the role of PGP9.5 over expression in lung epithelium to EMU induced lung carcinogenesis. Our second line of study involving functional analysis of SMAD6 protein for its role in lung cancers progression. Using immunohistochemical analysis we showed that SMAD6 expression in lung tumors is associated with an increase in tumor recurrence in adenocarcinomas. We propose that this is due to reduction if negative growth signaling by TGF-beta/BMP upon SMAD6 expression. We have used siRNA approach to show that down regulation of SMAD6 lead to reduced cell growth in lung tumor cells but not minimally tranformed normal lung epithelial cells. This result suggeststs that SMAD6 might be used as a therapeutic target got lung cancer.